U.S. patent application number 10/580283 was filed with the patent office on 2007-11-22 for quinazoline derivative and process for producing the same.
This patent application is currently assigned to MITSUBISHI PHARMA CORPORATION. Invention is credited to Hiroshi Iwamura, Takashi Naka.
Application Number | 20070270589 10/580283 |
Document ID | / |
Family ID | 34631568 |
Filed Date | 2007-11-22 |
United States Patent
Application |
20070270589 |
Kind Code |
A1 |
Iwamura; Hiroshi ; et
al. |
November 22, 2007 |
Quinazoline Derivative and Process for Producing the Same
Abstract
Object: To offer novel quinazoline derivatives, which are useful
as intermediates in the production of agents for the treatment and
prevention of cancer, and an industrially useful method for
manufacture of the same. Means: The quinazoline derivative
represented by general formula (I) below: ##STR1## (in the formula,
each of the symbols is the same as described in the specification)
or a salt thereof, or a hydrate or solvate thereof, and a method
for using the same to produce novel quinazoline derivatives.
Inventors: |
Iwamura; Hiroshi; (Tokyo,
JP) ; Naka; Takashi; (Tokyo, JP) |
Correspondence
Address: |
COLEMAN SUDOL SAPONE, P.C.
714 COLORADO AVENUE
BRIDGE PORT
CT
06605-1601
US
|
Assignee: |
MITSUBISHI PHARMA
CORPORATION
6-9, Hiranomachi 2-chome
Chuo-ku, Osaka-shi
JP
541-0046
|
Family ID: |
34631568 |
Appl. No.: |
10/580283 |
Filed: |
November 26, 2004 |
PCT Filed: |
November 26, 2004 |
PCT NO: |
PCT/JP04/17564 |
371 Date: |
March 16, 2007 |
Current U.S.
Class: |
544/293 |
Current CPC
Class: |
C07D 239/94
20130101 |
Class at
Publication: |
544/293 |
International
Class: |
C07D 239/72 20060101
C07D239/72 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 28, 2003 |
JP |
2003-398442 |
Claims
1. A quinazoline derivative represented by general formula (I)
below, or a salt thereof, or a hydrate or solvate thereof:
##STR31## [in the formula, m denotes an integer from 0 to 3,
R.sup.1 denotes a hydrogen atom, halogen atom, hydroxy group, cyano
group, nitro group, trifluoromethyl group, C.sub.1 to C.sub.5 alkyl
group, C.sub.1 to C.sub.5 alkoxy group, --S(O).sub.fR.sup.12 (in
the formula, f denotes an integer from 0 to 2, R.sup.12 denotes a
C.sub.1 to C.sub.5 alkyl group), --NR.sup.13R.sup.14 (in the
formula, R.sup.13 and R.sup.14 each individually denotes a hydrogen
atom, C.sub.1 to C.sub.5 alkyl group, C.sub.1 to C.sub.5 alkanoyl
group, or C.sub.1 to C.sub.5 alkylsulfonyl group), C.sub.2 to
C.sub.5 alkenyl group, or C.sub.2 to C.sub.5 alkynyl group, and
either one of R.sup.2 and R.sup.3 denotes general formula (II)
below ##STR32## (in the formula, R.sup.4, R.sup.5 and R.sup.6 each
individually denotes a hydrogen atom, C.sub.1 to C.sub.5 alkyl
group that may have substituents, C.sub.7 to C.sub.12 aralkyl group
that may have substituents, or C.sub.6 to C.sub.10 aryl group that
may have substituents, R.sup.7 denotes --SO.sub.2R.sup.15,
--SOR.sup.15, or --OR.sup.15 (in the formula, R.sup.15 denotes a
C.sub.1 to C.sub.5 alkyl group that may have substituents, C.sub.7
to C.sub.12 aralkyl group that may have substituents, or C.sub.6 to
C.sub.10 aryl group that may have substituents) and the remaining
one of R.sup.2 and R.sup.3 denotes an iodine atom or general
formula (III) below: ##STR33## (in the formula, R.sup.8 and R.sup.9
each individually denotes a hydrogen atom, or a C.sub.1 to C.sub.5
alkyl group that may be substituted with a hydroxyl group or
C.sub.1 to C.sub.5 alkoxy group, p denotes an integer from 0 to 3,
R.sup.10 and R.sup.11 each individually denotes a hydrogen atom or
C.sub.1 to C.sub.5 alkyl group, Y denotes a hydrogen atom, hydroxyl
group, C.sub.1 to C.sub.5 alkoxy group, C.sub.1 to C.sub.5
alkanoyloxy group, piperazin-1-yl that has a C.sub.1 to C.sub.5
alkyl group that may be substituted at the 4-position, or an amino
that is di-substituted with C.sub.1 to C.sub.5 alkyls that may be
substituted), and herein, when m denotes 2 or 3, R.sup.1 may be the
same or different.]
2. The quinazoline derivative, salt thereof, or hydrate or solvate
thereof according to claim 1, wherein m is 2, R.sup.1 is a halogen
atom, R.sup.2 is --NHCO--CH.sub.2--CH.sub.2--R.sup.7 (in the
formula, R.sup.7 denotes a methylsulfonyl group, benzenesulfonyl
group, phenyloxy group, phenylthio group, or methylthio group), and
R.sup.3 is an iodine atom or general formula (IV) below: ##STR34##
(in the formula, R.sup.8' and R.sup.9' each individually denotes a
hydrogen atom, methyl group, ethyl group, propyl group, or
isopropyl group, and Y' denotes a morpholino group or
4-methylpiperazin-1-yl).
3. The quinazoline derivative, salt thereof, or hydrate or solvate
thereof according to either claim 1 or 2, selected from a group
consisting of the following compounds:
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl
}-3-(phenylsulfonyl)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl
}-3-(phenyloxy)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl}-3-(phenylsulfonyl)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl}-3-(phenyloxy)propanamide.
4. The quinazoline derivative, salt thereof, or hydrate or solvate
thereof according to claim 3, wherein the compound is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide.
5. A method for preparing the quinazoline derivative represented by
general formula (I) of claim 1 [where either of R.sup.2 and R.sup.3
denotes general formula (II) of claim 1, and the other of R.sup.2
and R.sup.3 denotes general formula (III) of claim 1], salt
thereof, or hydrate or solvate thereof, by allowing the quinazoline
derivative represented by general formula (V) below: ##STR35## [in
the formula, m and R.sup.1 are the same as in claim 1, either one
of R.sup.2a and R.sup.3a is defined the same as in general formula
(II) of claim 1, and the other of R.sup.2a and R.sup.3a denotes an
iodine atom], or salt thereof, or hydrate or solvate thereof to
react with a compound represented by general formula (VI) below:
##STR36## (in the formula, R.sup.8, R.sup.9, R.sup.10, R.sup.11, Y
and p are defined the same as in claim 1), or salt thereof, or
hydrate or solvate thereof.
6. The preparation method according to claim 5, wherein m is 2,
R.sup.1 is a halogen atom, R.sup.2a is
--NHCO--CH.sub.2--CH.sub.2--R.sup.7 (in the formula, R.sup.7
denotes a methylsulfonyl group, benzenesulfonyl group, phenyloxy
group, phenylthio group, or methylthio group), and R.sup.3 is an
iodine atom.
7. The preparation method according to claim 5, wherein the
quinazoline derivative represented by general formula (V) is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide or
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenyloxy-
)propanamide.
8. The preparation method according to claim 7, wherein the
quinazoline derivative is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide.
9. A method for preparing the compound represented by general
formula (III) of claim 1, a pharmaceutically acceptable salt
thereof, or a hydrate or solvate thereof, using any of the
compounds recited in claim 1-4, represented by general formula
(VII) below: ##STR37## [in the formula, m and R.sup.1 are defined
the same as in claim 1, either one of R.sup.16 and R.sup.17 denotes
--NHCO--CR.sup.4.dbd.CR.sup.5R.sup.6 (in the formula, R.sup.4,
R.sup.5, and R.sup.6 are defined the same as in claim 1), and the
other one of R.sup.16 and R.sup.17 is.
10. The preparation method according to claim 9, wherein m is 2,
R.sup.1 is a halogen, R.sup.2 is --NHCO--CH.sub.2CH.sub.2--R.sup.7,
R.sup.16 is --NHCO--CH.dbd.CH.sub.2, and R.sup.3 and R.sup.17 are
general formula (IV) of claim 2.
11. The preparation method according to claim 10, wherein R.sup.8
and R.sup.9 each individually is a methyl group, and Y' is
4-methylpiperazin-1-yl.
12. The preparation method for the compound represented by general
formula (VII) of claim 9, salt thereof, or hydrate or solvate
thereof comprising the preparation method according to any of
claims 5 to 11.
13. The preparation method according to claim 12, wherein m is 2,
R.sup.1 is a halogen, R.sup.2 is --NHCO--CH.sub.2CH.sub.2--R.sup.7,
R.sup.16 is --NHCO--CH.dbd.CH.sub.2, and R.sup.3 and R.sup.17 are
general formula (IV) of claim 2.
14. The preparation method according to claim 12, wherein R.sup.8'
and R.sup.9' each individually is a methyl group, and Y' is
4-methylpiperazin-1-yl.
15. The compound represented by general formula (VIII) below:
##STR38## [in the formula, either of R.sup.18 and R.sup.19 denotes
a nitro group, amino group, hydroxyamino group, or
--NHCO--CH.sub.2CH.sub.2--R.sup.7' (in the formula, R.sup.7'
denotes a methylsulfonyl group, benzenesulfonyl group, phenyloxy
group, phenylthio group, or methylthio group), and the remaining
one of R.sup.18 and R.sup.19 denotes an iodine atom, and R.sup.20
denotes a hydrogen atom, 3,4-dimethoxybenzyl group, 4-methoxybenzyl
group, benzyloxymethyl group, or trifluoroacetyl group], a salt
thereof, or a hydrate or solvate thereof.
16. A compound, salt thereof, or hydrate or solvate thereof
according to claim 15, selected from a group consisting of the
following compounds:
7-iodo-3-(4-methoxybenzyl)-6-nitro-4-quinazolinone,
6-amino-7-iodo-3-(4-methoxybenzyl)-4-quinazolinone,
N-[7-iodo-3-(4-methoxybenzyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-3-(phenyl-
sulfonyl)propanamide,
N-[7-iodo-3-(4-methoxybenzyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-3-(phenyl-
oxy)propanamide,
N-(7-iodo-4-oxo-3,4-dihydro-6-quinazolinyl)-3-(phenylsulfonyl)propanamide-
, and
N-(7-iodo-4-oxo-3,4-dihydro-6-quinazolinyl)-3-(phenyloxy)propanamide-
.
17. The compound, salt thereof, or hydrate or solvate thereof
according to claim 16, wherein the compound is
7-iodo-3-(4-methoxybenzyl)-6-nitro-4-quinazolinone,
6-amino-7-iodo-3-(4-methoxybenzyl)-4-quinazolinone,
N-[7-iodo-3-(4-methoxybenzyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-3-(phenyl-
sulfonyl)propanamide, or
N-(7-iodo-4-oxo-3,4-dihydro-6-quinazolinyl)-3-(phenylsulfonyl)propanamide-
.
18. The preparation method for the compound of general formula (I)
in claim 1 which uses any of the compounds according to any of
claims 15 to 17.
19. The preparation method according to claim 18, wherein m is 2,
R.sup.1 is a halogen atom, R.sup.2 is
--NHCO--CH.sub.2--CH.sub.2--R.sup.7 (in the formula, R.sup.7
denotes a methylsulfonyl group, benzenesulfonyl group, phenyloxy
group, phenylthio group, or methylthio group), and R.sup.3 is an
iodine atom or general formula (IV) below: ##STR39## (in the
formula, R.sup.8 and R.sup.9 each individually denotes a hydrogen
atom, methyl group, ethyl group, propyl group, or isopropyl group,
and Y' denotes a morpholino group or 4-methylpiperazin-1-yl).
20. The preparation method according to claim 18, wherein the
compound is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenyloxy-
)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl}-3-(phenylsulfonyl)propanamide, or
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl}-3-(phenyloxy)propanamide.
21. The preparation method according to claim 18, wherein the
compound is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide.
22. The method for preparing a compound represented by general
formula (V) according to claim 5, comprising a step in which a
compound represented by general formula (IX) below: ##STR40## [in
the formula, either one of R.sup.18 and R.sup.19 denotes general
formula (II) of claim 1, and the remaining one of R.sup.18 and
R.sup.19 denotes an iodine atom] is chlorinated to produce a
compound represented by general formula (X) below: ##STR41## (in
the formula, R.sup.18 and R.sup.19 are defined the same as above),
and a step in which a compound represented by general formula (XI)
below: ##STR42## (in the formula, m and R.sup.1 are the defined
same as in claim 1) is added.
23. A quinazoline derivative represented by general formula (XII)
below: ##STR43## (in the formula, m and R.sup.1 are defined the
same as in claim 1, either one of R.sup.21 and R.sup.22 denotes an
amino group or nitro group, and the remaining one of R.sup.21 and
R.sup.22 denotes an iodine atom), a salt thereof, or a hydrate or
solvate thereof.
24. A method for preparing a compound represented by general
formula (I) of claim 1, a pharmaceutically acceptable salt thereof,
a hydrate or solvate thereof, wherein the nitro group of a compound
wherein either one of R.sup.21 and R.sup.22 in general formula
(XII) of claim 23 is a nitro group and the other one of R.sup.21
and R.sup.22 is an iodine atom is changed to an amino group,
whereupon a reaction is allowed to occur with a compound of general
formula (XIII) below: ##STR44## (in the formula, R.sup.4, R.sup.5,
R.sup.6 and R.sup.7 are defined the same as in claim 1).
Description
TECHNICAL FIELD
[0001] The present invention relates to novel quinazoline
derivatives that are useful as synthesis intermediates for
pharmaceuticals and physiologically active substances, particularly
as intermediates in the production of agents for the treatment and
prevention of cancer, and to a method for production of the
same.
BACKGROUND ART
[0002] Quinazoline derivatives represented by general formula (1a):
##STR2## {The reference symbols in the formula are such that, for
example, m denotes an integer of 1 or 2, R.sup.1 denotes a halogen
atom, either R' or R'' denotes: ##STR3## (In the formula, X denotes
--C(O)--, and R.sup.4, R.sup.5 and R.sup.6 each individually
denotes a C.sub.1 to C.sub.5 alkyl that may be substituted.), and
the remaining one of R.sup.2 and R.sup.3 denotes: ##STR4## [In the
formula, m' denotes an integer from 0 to 3, R.sup.8 and R.sup.9
each individually denotes a C.sub.1 to C.sub.5 alkyl that may be
substituted, R.sup.11 and R.sup.12 each individually denotes a
hydrogen atom or C.sub.1 to C.sub.5 alkyl, Y denotes: ##STR5## (In
the formula, p and q each individually denotes an integer of 2 or
3, and Z denotes --O-- or a carbonyl.)]} exhibit inhibitory action
with respect to both the EGF receptor and the HER2 receptor (dual
inhibitory actions), and are known to have cancer cell growth
inhibitory actions (see Patent Document 1).
[0003] A known general synthesis example for this type of
quinazoline derivative involves, for example, a reaction between a
quinazoline compound, wherein R' is a nitro group or amino group
and R'' is a chlorine atom or bromine atom, and a substituted
alkyne compound in the presence of a metal reagent such as Pd to
produce an alkynyl quinazoline derivative, followed by conversion
to the corresponding amino compound, followed by derivation of a
vinylamide.
[0004] In the above method, the reaction in which the quinazoline
compound and alkyne compound bond together is carried out under
high-temperature conditions.
[0005] Furthermore, in the reaction that generates a carbon-carbon
bond using a Pd catalyst, various investigations have been carried
out regarding reaction conditions in the vicinity of room
temperature, but all of these use costly unstable reagents (see
Non-Patent Document 1). For this reason, there is need for the
discovery of a simple technique for obtaining and handling the
reagent in order to carry out this reaction on an industrial
scale.
[0006] In addition to the above, it has not been possible to
achieve adequate yields in the step in which the aminoquinazoline
derivative is converted to the vinylamide quinazoline
derivative.
[0007] The yield of vinylamidation of the amino groups of the
aminoquinazoline derivative is generally known to be low (see
Non-Patent Documents 2 and 3). It has been hypothesized that
polymerization by way of the vinyl groups may be a factor, and
details regarding a similar reaction with an oxazolidinone
derivative have been reported (see Non-Patent Documents 4 and
5).
[0008] In light of the above, there is need for the discovery of a
synthesis method for alkynyl quinazoline derivatives as well as a
technique for increasing the yield at which vinylamide groups are
created in order to produce vinylamidoquinazoline derivatives on an
industrial scale.
[0009] Patent Document 1: International Publication WO
02/066445.
[0010] Non-Patent Document 1: Org. Lett., 2000, 2, 1729.
[0011] Non-Patent Document 2: J. Med. Chem., 1999, 42, 1803.
[0012] Non-Patent Document 3: J. Med. Chem., 2000, 43, 1387.
[0013] Non-Patent Document 4: Tetrahedron Lett., 1996, 52,
13523.
[0014] Non-Patent Document 5: J. Org. Chem., 1995, 60, 2271.
DISCLOSURE OF THE INVENTION
Problems to Be Solved by the Invention
[0015] It is necessary to solve problems such as those described
above in order to industrially produce quinazoline derivatives of
the type represented by general formula (1a).
[0016] Specifically, an object of the present invention is to
provide an industrially advantageous production method and a novel
synthesis intermediate in this production method by means of (1)
relaxing the conditions for the reaction between the quinazoline
compound and alkyne compound, and (2) creating vinylamide groups at
higher yields.
Means for Solving the Problems
[0017] In the Pd catalyst oxidative addition reaction, it is known
that the corresponding iodo compounds have higher reactivity than
the bromo compounds and chloro compounds for organic halides
substituted with SP2 carbons (Palladium Reagent and Catalysts,
Tsuji, J. Eds.; John Wiley & Sons: Chichester, 1995; Chapter
1).
[0018] The present inventors investigated reactions between
quinazoline derivatives represented by general formula (I) below:
##STR6## (In the formula, m denotes an integer from 0 to 3, R.sup.1
denotes a hydrogen atom, halogen atom, hydroxy group, cyano group,
nitro group, trifluoromethyl group, C.sub.1 to C.sub.5 alkyl group,
C.sub.1 to C.sub.5 alkoxy group, --S(O).sub.fR.sup.12 (In the
formula, f denotes an integer from 0 to 2 and R.sup.12 denotes a
C.sub.1 to C.sub.5 alkyl group.), --NR.sup.13R.sup.14 (In the
formula, R.sup.13 and R.sup.14 each individually denotes a hydrogen
atom, C.sub.1 to C.sub.5 alkyl group, C.sub.1 to C.sub.5 alkanoyl
group, or C.sub.1 to C.sub.5 alkylsulfonyl group.), C.sub.2 to
C.sub.5 alkenyl group, or C.sub.2 to C.sub.5 alkynyl group, and
either one of R.sup.2 and R.sup.3 denotes general formula (II)
below: ##STR7## (In the formula, R.sup.4, R.sup.5 and R.sup.6 each
individually denotes a hydrogen atom, C.sub.2 to C.sub.5 alkyl
group that may have substituents, C.sub.7 to C.sub.12 aralkyl group
that may have substituents, or C.sub.6 to C.sub.10 aryl group that
may have substituents, R.sup.7 denotes --SO.sub.2R.sup.15,
--SOR.sup.15, or --OR.sup.15 (In the formula, R.sup.15 denotes a
C.sub.1 to C.sub.5 alkyl group that may have substituents, C.sub.7
to C.sub.12 aralkyl group that may have substituents, or C.sub.6 to
C.sub.10 aryl group that may have substituents) and the remaining
one of R.sup.2 and R.sup.3 denotes an iodine atom. Note that each
R.sup.1 may be the same or different when m denotes 2 or 3.) and
alkyne compounds represented by general formula (VII): ##STR8## (In
the formula, R.sup.8a and R.sup.9a each individually denotes a
hydrogen atom, or a C.sub.1 to C.sub.5 alkyl group that may be
substituted with a hydroxyl group or C.sub.1 to C.sub.5 alkoxy
group, p denotes an integer from 0 to 3, R.sup.10a and R.sup.11a
each individually denotes a hydrogen atom or C.sub.1 to C.sub.5
alkyl group, Y.sup.a denotes a hydrogen atom, hydroxy group,
C.sub.1 to C.sub.5 alkoxy group, C.sub.1 to C.sub.5 alkanoyloxy
group, piperazin-1-yl that has a C.sub.1 to C.sub.5 alkyl group
that may be substituted at the 4-position, or an amino that is
disubstituted with C.sub.1 to C.sub.5 alkyls that may be
substituted).
[0019] As a result, by using the corresponding iodo compound, a
coupling reaction was successfully carried out between the
quinazoline compound (I) and alkyne compound (VII) under conditions
that were more industrially advantageous than those with the chloro
compound or bromo compound.
[0020] Furthermore, the present inventors attempted to improve
yields by suppressing polymerization of the vinylamide quinazoline
derivative or the like during production of the vinylamide
quinazoline derivative. Specifically, the conversion reaction was
successfully carried out at high yield and under mild conditions,
and the present invention was realized as a result of
investigations involving the production of a quinazoline derivative
substituted at the .beta.-position with a labile functional group
such as compound represented by general formula (VIII) ##STR9## {In
the formula, m' and R.sup.1a are the same as m and R.sup.1 in
general formula (I) above, and either one of R.sup.16 and R.sup.17
denotes general formula (IX) below: ##STR10## [In the formula,
R.sup.4a, R.sup.5a and R.sup.6a are the same as in general formula
(II) above, and R.sup.7a denotes --SO.sub.2R.sup.15, --SOR.sup.15,
or --OR.sup.15 (In the formula, R.sup.15 denotes a C.sub.1 to
C.sub.5 alkyl group that may have substituents, a C.sub.7 to
C.sub.12 aralkyl group that may have substituents, or a C.sub.6 to
C.sub.10 aryl group that may have substituents.).], and the other
of R.sup.16 and R.sup.17 denotes general formula (X) below:
##STR11## (In the formula, each of the symbols is the same as in
general formula (VII) above.).}, followed by conversion to the
vinylamidoquinazoline derivative represented by general formula
(XI): ##STR12## [In the formula, m' and R.sup.1a are the same as in
general formula (VIII) above, either one of R.sup.18 and R.sup.19
denotes --NHCO--CR.sup.4a=CR.sup.5aR.sup.6a (In the formula,
R.sup.4a, R.sup.5a and R.sup.6a are the same as in general formula
(IX) above.), and the other of R.sup.18 and R.sup.19 denotes
general formula (XII) below: ##STR13## (In the formula, each of the
symbols is the same as in general formula (X) above.).].
EFFECT OF THE INVENTION
[0021] By virtue of the present invention, a novel quinazoline
derivative can be provided for use as an intermediate in the
production of pharmaceutical products such as cancer drugs.
Furthermore, the quinazoline derivative can be used in order to
provide an efficient production method for pharmaceutical
products.
BEST MODE FOR CARRYING OUT THE INVENTION
[0022] Specifically, the gist of the present invention relates to
(1) to (24) below.
[0023] (1) A quinazoline derivative represented by general formula
(I) below, or a salt thereof, or a hydrate or solvate thereof:
##STR14## [In the formula, m denotes an integer from 0 to 3,
R.sup.1 denotes a hydrogen atom, halogen atom, hydroxy group, cyano
group, nitro group, trifluoromethyl group, C.sub.1 to C.sub.5 alkyl
group, C.sub.1 to C.sub.5 alkoxy group, --S(O).sub.fR.sup.12 (in
the formula, f denotes an integer from 0 to 2, R.sup.12 denotes a
C.sub.1 to C.sub.5 alkyl group), --NR.sup.13R.sup.14 (in the
formula, R.sup.13 and R.sup.14 each individually denotes a hydrogen
atom, C.sub.1 to C.sub.5 alkyl group, C.sub.1 to C.sub.5 alkanoyl
group, or C.sub.1 to C.sub.5 alkylsulfonyl group), C.sub.2 to
C.sub.5 alkenyl group, or C.sub.2 to C.sub.5 alkynyl group, and
either one of R.sup.2 and R.sup.3 denotes general formula (II)
below ##STR15## (In the formula, R.sup.4, R.sup.5 and R.sup.6 each
individually denotes a hydrogen atom, C.sub.1 to C.sub.5 alkyl
group that may have substituents, C.sub.7 to C.sub.12 aralkyl group
that may have substituents, or C.sub.6 to C.sub.10 aryl group that
may have substituents, R.sup.7 denotes --SO.sub.2R.sup.15,
--SOR.sup.5, or --OR.sup.15 (in the formula, R.sup.15 denotes a
C.sub.1 to C.sub.5 alkyl group that may have substituents, C.sub.7
to C.sub.12 aralkyl group that may have substituents, or C.sub.6 to
C.sub.10 aryl group that may have substituents.) and the remaining
one of R.sup.2 and R.sup.3 denotes an iodine atom or general
formula (III) below: ##STR16## (In the formula, R.sup.8 and R.sup.9
each individually denotes a hydrogen atom, or a C.sub.1 to C.sub.5
alkyl group that may be substituted with a hydroxyl group or
C.sub.1 to C.sub.5 alkoxy group, p denotes an integer from 0 to 3,
R.sup.10 and R.sup.11 each individually denotes a hydrogen atom or
C.sub.1 to C.sub.5 alkyl group, Y denotes a hydrogen atom, hydroxyl
group, C.sub.1 to C.sub.5 alkoxy group, C.sub.1 to C.sub.5
alkanoyloxy group, piperazin-1-yl that has a C.sub.1 to C.sub.5
alkyl group that may be substituted at the 4-position, or an amino
that is di-substituted with C.sub.1 to C.sub.5 alkyls that may be
substituted.), and herein, when m denotes 2 or 3, R.sup.1 may be
the same or different.].
[0024] (2) The quinazoline derivative, salt thereof, or hydrate or
solvate thereof according to (1) above, wherein m is 2, R.sup.1 is
a halogen atom, R.sup.2 is --NHCO--CH.sub.2--CH.sub.2--R.sup.7 (in
the formula, R.sup.7 denotes a methylsulfonyl group,
benzenesulfonyl group, phenyloxy group, phenylthio group, or
methylthio group), and R.sup.3 is an iodine atom or general formula
(IV) below: ##STR17## (In the formula, R.sup.8 and R.sup.9 each
individually denotes a hydrogen atom, methyl group, ethyl group,
propyl group, or isopropyl group, and Y' denotes a morpholino group
or 4-methylpiperazin-1-yl.).
[0025] (3) The quinazoline derivative, salt thereof, or hydrate or
solvate thereof according to either (1) or (2) above, selected from
a group consisting of the following compounds: [0026]
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenyloxy-
)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl}-3-(phenylsulfonyl)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl}-3-(phenyloxy)propanamide.
[0027] (4) The quinazoline derivative, salt thereof, or hydrate or
solvate thereof according to (3) above, wherein the compound is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide.
[0028] (5) A method for preparing the quinazoline derivative
represented by general formula (I) of (1) above [where either of
R.sup.2 and R.sup.3 denotes general formula (II) of (1) above, and
the other of R.sup.2 and R.sup.3 denotes general formula (III) of
(1) above], salt thereof, or hydrate or solvate thereof, by
allowing the quinazoline derivative represented by general formula
(V) below: ##STR18## [In the formula, m and R.sup.1 are the same as
in (1) above, either one of R.sup.2a and R.sup.3a is defined the
same as in general formula (II) of (1) above, and the other of
R.sup.2a and R.sup.3a denotes an iodine atom.], or salt thereof, or
hydrate or solvate thereof to react with a compound represented by
general formula (VI) below: ##STR19## (In the formula, the
reference numerals are the same as defined for general formula
(III) in (1) above.), or salt thereof, or hydrate or solvate
thereof.
[0029] (6) The preparation method according to (5) above, wherein m
is 2, R.sup.1 is a halogen atom, R.sup.2a is
--NHCO--CH.sub.2--CH.sub.2--R.sup.7 (in the formula, R.sup.7
denotes a methylsulfonyl group, benzenesulfonyl group, phenyloxy
group, phenylthio group, or methylthio group), and R.sup.3 is an
iodine atom.
[0030] (7) The preparation method according to (5) above, wherein
the quinazoline derivative represented by general formula (V) is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide or
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenyloxy-
)propanamide.
[0031] (8) The preparation method according to (7) above, wherein
the quinazoline derivative is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide.
[0032] (9) A method for preparing the compound represented by
general formula (III) of (1) above, a pharmaceutically acceptable
salt thereof, or a hydrate or solvate thereof, using any of the
compounds recited in (1) to (4) above, represented by general
formula (VII) ##STR20## [In the formula, m and R.sup.1 are defined
the same as in (1) above, either one of R.sup.16 and R.sup.17
denotes --NHCO--CR.sup.4.dbd.CR.sup.5R.sup.6 (in the formula,
R.sup.4, R.sup.5, and R.sup.6 are defined the same as in (1)
above), and the other one of R.sup.16 and R.sup.17 is.
[0033] (10) The preparation method according to (9) above, wherein
m is 2, R.sup.1 is a halogen, R.sup.2 is
--NHCO--CH.sub.2CH.sub.2--R.sup.7, R.sup.16 is
--NHCO--CH.dbd.CH.sub.2, and R.sup.3 and R.sup.17 are general
formula (IV) of (2) above.
[0034] (11) The preparation method according to (10) above, wherein
R.sup.8' and R.sup.9' each individually is a methyl group, and Y'
is 4-methylpiperazin-1-yl.
[0035] (12) The preparation method for the compound represented by
general formula (VII) of (9) above, salt thereof, or hydrate or
solvate thereof comprising the preparation method according to any
of (5) to (11) above.
[0036] (13) The preparation method according to (12) above, wherein
m is 2, R.sup.1 is a halogen, R.sup.2 is
--NHCO--CH.sub.2CH.sub.2--R.sup.7, R.sup.16 is
--NHCO--CH.dbd.CH.sub.2, and R.sup.3 and R.sup.17 are general
formula (IV) of (2) above.
[0037] (14) The preparation method according to (12) above, wherein
R.sup.8 and R.sup.9 each individually is a methyl group, and Y' is
4-methylpiperazin-1-yl.
[0038] (15) The compound represented by general formula (VIII)
below: ##STR21## [In the formula, either of R.sup.18 and R.sup.19
denotes a nitro group, amino group, hydroxyamino group, or
--NHCO--CH.sub.2CH.sub.2--R.sup.7' (in the formula, R.sup.7'
denotes a methylsulfonyl group, benzenesulfonyl group, phenyloxy
group, phenylthio group, or methylthio group), and the remaining
one of R.sup.18 and R.sup.19 denotes an iodine atom, and R.sup.20
denotes a hydrogen atom, 3,4-dimethoxybenzyl group, 4-methoxybenzyl
group, benzyloxymethyl group, or trifluoroacetyl group.], a salt
thereof, or a hydrate or solvate thereof. (16) A compound, salt
thereof, or hydrate or solvate thereof according to (15) above,
selected from a group consisting of the following compounds: [0039]
7-iodo-3-(4-methoxybenzyl)-6-nitro-4-quinazolinone,
6-amino-7-iodo-3-(4-methoxybenzyl)-4-quinazolinone,
N-[7-iodo-3-(4-methoxybenzyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-3-(phenyl-
sulfonyl)propanamide,
N-[7-iodo-3-(4-methoxybenzyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-3-(phenyl-
oxy)propanamide,
N-(7-iodo-4-oxo-3,4-dihydro-6-quinazolinyl)-3-(phenylsulfonyl)propanamide-
, and
N-(7-iodo-4-oxo-3,4-dihydro-6-quinazolinyl)-3-(phenyloxy)propanamide-
.
[0040] (17) The compound, salt thereof, or hydrate or solvate
thereof according to (16) above, wherein the compound is
7-iodo-3-(4-methoxybenzyl)-6-nitro-4-quinazolinone,
6-amino-7-iodo-3-(4-methoxybenzyl)-4-quinazolinone,
N-[7-iodo-3-(4-methoxybenzyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-3-(phenyl-
sulfonyl)propanamide, or
N-(7-iodo-4-oxo-3,4-dihydro-6-quinazolinyl)-3-(phenylsulfonyl)propanamide-
.
[0041] (18) The preparation method for the compound of general
formula (I) in (1) above which uses any of the compounds according
to any of (15) to (17) above.
[0042] (19) The preparation method according to (18) above, wherein
m is 2, R.sup.1 is a halogen atom, R.sup.2 is
--NHCO--CH.sub.2--CH.sub.2--R.sup.7 (in the formula, R.sup.7
denotes a methylsulfonyl group, benzenesulfonyl group, phenyloxy
group, phenylthio group, or methylthio group), and R.sup.3 is an
iodine atom or general formula (IV) below: ##STR22## (In the
formula, R.sup.8' and R.sup.9' each individually denotes a hydrogen
atom, methyl group, ethyl group, propyl group, or isopropyl group,
and Y' denotes a morpholino group or 4-methylpiperazin-1-yl.).
[0043] (20) The preparation method according to (18) above, wherein
the compound is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenyloxy-
)propanamide,
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl)-3-(phenylsulfonyl)propanamide, or
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl}-3-(phenyloxy)propanamide.
[0044] (21) The preparation method according to (18) above, wherein
the compound is
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide.
[0045] (22) The method for preparing a compound represented by
general formula (V) according to (5) above, comprising a step in
which a the compound represented by general formula (IX) below:
##STR23## [In the formula, either one of R.sup.18 and R.sup.19
denotes general formula (II) of (1) above, and the remaining one of
R.sup.18 and R.sup.19 denotes an iodine atom.] is chlorinated to
produce a compound represented by general formula (X) below:
##STR24## (In the formula, R.sup.18 and R.sup.19 are defined the
same as above.), and a step in which a compound represented by
general formula (XI) below: ##STR25## (In the formula, m and
R.sup.1 are the defined same as in (1) above.) is added.
[0046] (23) A quinazoline derivative represented by general formula
(XII) below: ##STR26## (In the formula, m and R.sup.1 are defined
the same as in (1) above, either one of R.sup.21 and R.sup.22
denotes an amino group or nitro group, and the remaining one of
R.sup.21 and R.sup.22 denotes an iodine atom.), a salt thereof, or
a hydrate or solvate thereof.
[0047] (24) A method for preparing a compound represented by
general formula (I) of (1) above, a pharmaceutically acceptable
salt thereof, a hydrate or solvate thereof, wherein the nitro group
of a compound wherein either one of R.sup.21 and R.sup.22 in
general formula (XII) of (23) above is a nitro group and the other
one of R.sup.21 and R.sup.22 is an iodine atom is changed to an
amino group, whereupon a reaction is allowed to occur with a
compound of general formula (XIII) below: ##STR27## (in the
formula, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are defined the same
as in (1) above).
[0048] Hereinbelow, the present invention is defined in detail.
[0049] Examples of halogens as defined in the present invention
include a fluorine atom, chlorine atom, bromine atom, or iodine
atom, examples of C.sub.1 to C.sub.5 alkyl groups include a methyl
group, ethyl group, n-propyl group, iso-propyl group, n-butyl
group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl
group, neopentyl group or the like, examples of C.sub.1 to C.sub.5
alkoxy groups include a methoxy group, ethoxy group, n-propoxy
group, iso-propoxy group, n-butoxy group, iso-butoxy group,
sec-butoxy group, tert-butoxy group, n-pentyloxy group,
neopentyloxy group or the like, examples of C.sub.2 to C.sub.5
alkenyl groups include a vinyl group, 1-propenyl group, 2-propenyl
group, 1-butenyl group, 2-methylpropen-1-yl group, 2-butenyl group,
1-pentenyl group, 2-pentenyl group or the like, examples of C.sub.2
to C.sub.5 alkynyl groups include an ethynyl group, 1-propynyl
group, 1-butynyl group, 1-pentynyl group or the like, examples of
C.sub.1 to C.sub.5 alkanoyl groups include a formyl group, acetyl
group, propionyl group, butyryl group, isovaleryl group, valeryl
group or the like, examples of C.sub.7 to C.sub.12 aralkyl groups
include a benzyl group, phenylethyl group, phenylpropyl group,
naphthylmethyl group or the like, and examples of C.sub.6 to
C.sub.10 aryl groups include a phenyl group, tolyl group, naphthyl
group, mesityl group, xylyl group or the like.
[0050] When the phrase "that may have substituents" is used in the
definition of substituents in the general formula above, examples
of substituents include C.sub.1 to C.sub.6 alkyl groups such as a
methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl
group, sec-butyl group, isobutyl group, tert-butyl group, n-pentyl
group, and n-hexyl group; C.sub.1 to C.sub.6 haloalkyl groups such
as a chloromethyl group, bromomethyl group, dichloromethyl group,
1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group,
4-chlorobutyl group, 5-chloropentyl group, 6-chlorohexyl group,
difluoromethyl group, and trifluoromethyl group; C.sub.1 to C.sub.6
alkoxy groups such as a methoxy group, ethoxy group, n-propoxy
group, isopropoxy group, n-butoxy group, sec-butoxy group,
isobutyloxy group, tert-butyloxy group, n-pentyloxy group, and
n-hexyloxy group; and halogen atoms such as a fluorine atom,
chlorine atom, and bromine atom.
[0051] Salts that may be cited include inorganic acid salts (such
as hydrochlorides, sulfates, carbonates, and phosphates), organic
acid salts (such as formates, acetates, propionates, lactates,
oxalates, fumarates, maleates, citrates, tartrates, benzoates,
phthalates, methanesulfonates, p-toluenesulfonates, isethionates,
glucuronates, and gluconates), alkali metal salts (such as sodium
salts and potassium salts), alkaline earth metal salts (such as
magnesium salts and calcium salts), ammonium salts, or salts with
organic amines (such as trimethylamine, triethylamine, benzylamine,
phenethylamine, monoethanolamine, diethanolamine,
tris(hydroxyethylamine), lysine, and arginine).
[0052] The quinazoline derivative of the present invention can have
various three-dimensional structures. For example, when an
asymmetric carbon atom is considered as the center, the absolute
configuration may be either (S) or (R), or a racemic form. Pure
optical isomer or diastereoisomer configurations, any mixture of
these isomers, and racemic forms are all within the scope of the
present invention.
[0053] Furthermore, the quinazoline derivative represented by
general formula (I) above may be present, for example, in the form
of a solvate such as a hydrate or in the form of a non-solvate, and
the present invention encompasses all of these types of solvate
forms that can be used in manufacture.
[0054] The compound represented by general formula (I) or (VII)
above, for example, can be used as an intermediate in the
production of agents for treating and preventing cancer.
[0055] An example of a production method according to the present
invention is described in further detail below.
[0056] Among the quinazoline derivatives represented by general
formula (I) above, quinazoline derivatives wherein either one of
R.sup.2 and R.sup.3 is represented by general formula (II) above
and the other is an iodine atom can be produced, for example, by
the method described below (route A). ##STR28##
[0057] Step 1 involves conversion of the chloro group of
quinazoline compound XIV'-1 (In the formula, the nitro group is
bonded at either the 6-position or 7-position of the quinazoline
ring, and the chloro group is bonded at the other of the 6-position
of 7-position of the quinazoline ring. This compound XIV'-1 can be
synthesized by the method described in J. Org. Chem., 1975, 40,
356. or the like) into XIV'-2 by means of a halogen exchange
reaction.
[0058] The halogen exchange reaction can be carried out by using 1
to 100, and preferably 5 to 30, equivalents of quaternary ammonium
salt (such as iodobenzyltriethylammonium) or inorganic iodine
compound typified by sodium iodide or potassium iodide.
[0059] The reaction may be carried out at -50 to 300.degree. C.,
and preferably 100 to 200.degree. C., in a hydrocarbon-based
solvent such as toluene, an ether-based solvent such as
tetrahydrofuran (hereinafter "THF"), methyltetrahydrofuran, or
ethylene glycol, an ester-based solvent such as ethyl acetate, or
isopropyl acetate, or an aprotic polar solvent such as an
N,N-dimethylformamide (hereinafter "DMF"),
1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone,
dimethylsulfoxide (hereinafter "DMSO"), or acetonitrile.
[0060] Step 2 is a step in which compound XIV-1 is derived by
allowing a reaction to occur at the 3-position of the quinazoline
ring of compound XIV'-2.
[0061] The reaction can be carried out using 0.8 to 100
equivalents, and preferably 1 to 5 equivalents, of
3,4-dimethoxybenzyl chloride, 3,4-dimethoxybenzyl bromide,
4-methoxybenzyl chloride, 4-methoxybenzyl bromide, benzyl
chloromethyl ether, or trifluoroacetic anhydride with respect to
compound XIV'-2.
[0062] The above reaction can be carried out in the presence or
absence of an organic base such as triethylamine,
diisopropylethylamine, N-methylmorpholine, pyridine, or
1,4-diazabicyclo[2.2.2]octane (hereinafter "DABCO"), or an
inorganic base such as potassium carbonate, sodium hydride,
potassium bicarbonate, sodium hydroxide, or potassium
phosphate.
[0063] The reaction can be carried out at -50 to 300, and
preferably 0 to 100.degree. C., in a hydrocarbon-based solvent such
as toluene, an ether-based solvent such as THF,
methyltetrahydrofuran, or ethylene glycol, an ester-based solvent
such as ethyl acetate, or isopropyl acetate, or an aprotic polar
solvent such as DMF, 1,3-dimethyl-2-imidazolidinone,
1-methyl-2-pyrrolidone, DMSO, or acetonitrile.
[0064] Step 3 is a step in which the nitro group of compound XIV-1
is reduced to derive compound XIV-2. The reaction can be carried
out in the presence or absence of 0.1 to 100 equivalents of
inorganic acid such as hydrochloric acid or sulfuric acid, or an
organic acid such as trifluoroacetic acid or acetic acid, with 0.8
to 100 equivalents, and preferably 1 to 5 equivalents of reduced
iron, zinc powder, tin chloride, or the like. Furthermore,
reduction can be carried out using 0.001 to 0.05 equivalent of
FeCl.sub.3 in the presence of 0.8 to 100 equivalents, and
preferably 1 to 5 equivalents, of hydrazine. Under these
conditions, the reaction can be carried out in the presence or
absence of activated carbon.
[0065] The reaction can also be carried out at -50 to 300.degree.
C., and preferably 0 to 100.degree. C. in a hydrocarbon-based
solvent such as toluene, an ether-based solvent such as THF,
methyltetrahydrofuran, or ethylene glycol, an ester-based solvent
such as ethyl acetate or isopropyl acetate, an aprotic polar
solvent such as DMF, 1,3-dimethyl-2-imidazolidinone,
1-methyl-2-pyrrolidone, DMSO, or acetonitrile, or an alcohol-based
solvent such as ethanol, methanol, isopropyl alcohol ("IPA" below),
propanol, or butanol or without a solvent.
[0066] Step 4 involves allowing a reaction to occur between
carbonic acid XX (Z=OH) or acid halide thereof and the amino group
of compound XIV-2, thereby producing the amide compound XIV-3
(R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as described above;
reference literature: Chem. Ber., 1924, 57, 202 and J. Am. Chem.
Soc., 1952, 74, 1323.).
[0067] The reaction is allowed to occur using 0.8 to 100
equivalents, and preferably 1 to 5 equivalents, of XX with respect
to compound XIV-2. When the Z in compound XX is --OH, then the
reaction is allowed to occur using 0.8 to 100 equivalents, and
preferably 1 to 10 equivalents, of a typical peptide bond-forming
reagent (such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride, N,N'-dicyclohexylcarbodiimide, 1-propylphosphonic
acid cyclic anhydride, diethyl chlorophosphate, isobutyl
chloroformate, pivaloyl chloride, or thionyl chloride).
[0068] Even when the Z of compound XX is --OH or --Cl, the reaction
can be carried out in the presence or absence of organic base (such
as triethylamine, diisopropylethylamine, pyridine,
N-methylmorpholine, or DABCO) or inorganic base (such as potassium
carbonate, sodium hydride, potassium bicarbonate, sodium hydroxide,
or potassium phosphate).
[0069] The reaction can be carried out at -50 to 200.degree. C.,
and preferably 0 to 50.degree. C. in a hydrocarbon-based solvent
such as toluene, an ether-based solvent such as THF,
methyltetrahydrofuran, or ethylene glycol, an ester-based solvent
such as ethyl acetate or isopropyl acetate, or an aprotic polar
solvent such as DMF, 1,3-dimethyl-2-imidazolidinone,
1-methyl-2-pyrrolidone, DMSO, or acetonitrile.
[0070] Step 5 is a step involving conversion of R.sup.22 of
compound XIV-3 (a 3,4-dimethoxybenzyl group, 4-methoxybenzyl group,
benzyloxymethyl group, or trifluoroacetyl group) into a hydrogen
atom. The reaction can be carried out at -50 to 300.degree. C., and
preferably 0 to 100.degree. C., in the presence of 0.1 to 100
equivalents of inorganic acid (such as hydrochloric acid or
sulfuric acid), or organic acid (such as trifluoroacetic acid or
acetic acid), in a hydrocarbon-based solvent such as toluene, an
ether-based solvent such as THF, methyltetrahydrofuran, or ethylene
glycol, an ester-based solvent such as ethyl acetate or isopropyl
acetate, an aprotic polar solvent such as DMF,
1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, DMSO, or
acetonitrile, an alcohol-based solvent such as ethanol, methanol,
IPA, propanol, or butanol, or without a solvent.
[0071] Step 6 is a reaction in which compound I-1 is produced by
allowing 0.8 to 100 equivalents, and preferably 0.9 to 5
equivalents, of aniline derivative XVIII to react after converting
the 4-position of the quinazoline ring of compound XIV-4 to a
chlorine atom. Chlorination of compound XIV-4 is carried out by
using 0.8 to 100 equivalents, and preferably 1 to 10 equivalents,
of a chlorination reagent that is commonly used, such as phosphorus
oxychloride, thionyl chloride, phosphorus trichloride, phosphorus
pentachloride, or N-chlorosuccinic acid imide. Furthermore, the
4-position of the quinazoline ring of compound XIV-4 can be
converted to a chlorine atom, even if a quaternary ammonium salt
such as tetramethylammonium chloride, tetraethylammonium chloride,
benzyltrimethylammonium chloride, or benzyltriethylammonium
chloride is used together with the chlorination reagent (Can. J.
Chem., 1981, 59, 2601.).
[0072] This reaction can also be carried out in the presence or
absence of an organic base (such as triethylamine,
diisopropylethylamine, pyridine, N-methylmorpholine, or DABCO), or
inorganic base (such as potassium carbonate, sodium hydride,
potassium bicarbonate, sodium hydroxide, or potassium
phosphate).
[0073] This reaction can be carried out at -50 to 200.degree. C.,
and preferably 0 to 100.degree. C., where the reaction solvent is a
hydrocarbon-based solvent such as toluene, an ether-based solvent
such as THF, methyltetrahydrofuran, or ethylene glycol, an
ester-based solvent such as ethyl acetate or isopropyl acetate, or
an aprotic polar solvent such as DMF,
1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, DMSO, or
acetonitrile.
[0074] Similarly, of the quinazoline derivatives represented by
general formula (I) above, quinazoline derivatives in which either
of R.sup.2 and R.sup.3 is represented by general formula (II) above
and the other is an iodine atom can be produced, for example, in
the manner described below (route B). ##STR29##
[0075] Step 7 is a step in which the aniline derivative XVIII is
allowed to react after conversion of the 4-position of the
quinazoline ring of compound XIV'-2 to a chlorine atom, thereby
producing compound XV-1. In this step, synthesis is possible by the
same method as in the process of Step 6.
[0076] Step 8 is a step in which the nitro group of compound XV-1
is reduced to derive compound XV-2. In this step, synthesis can be
carried out in the same manner as in the process of Step 3.
[0077] Step 9 is a step in which carboxylic acid XX (Z=OH) or acid
halide thereof is allowed to react with the amino group of compound
XV-2, thereby producing an amide I-1. In this step, synthesis is
possible by the same method as Step 4.
[0078] A quinazoline derivative having vinylamide bonding of the
type represented by general formula (VII) can be produced in the
same manner as below from I-1 in which either R.sup.2 or R.sup.3 in
general formula (I) is represented by general formula (II) above
and the other is an iodine atom (route C). ##STR30##
[0079] Step 10 is a step in which compound VIII-1 is produced by
allowing the iodine atom of compound I-1 to react with compound VII
using a Pd catalyst in the presence of a copper salt. The reaction
is carried out in the presence of 0.001 to 1 equivalent, and
preferably 0.001 to 0.2 equivalent, of a monovalent copper salt
such as copper chloride, copper bromide, or copper iodide with
respect to compound I-1, and in the presence of palladium conjugate
prepared from 0 to 1 equivalent, and preferably 0 to 0.4
equivalent, of unidentate phosphine ligand such as
triphenylphosphine, tributylphosphine, or tri-tert-butylphosphine,
or bidentate phosphine ligand such as
1,1'-bis(diphenylphosphino)ferrocene,
1,3-bis(biphenylphosphino)propane,
1,2-bis(diphenylphosphino)ethane, 1,4-bis(diphenylphosphino)butane,
(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, or
(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl on 0.001 to 1
equivalent, and preferably 0.001 to 0.2 equivalent, of 0-valent or
divalent palladium catalyst such as palladium chloride, palladium
acetate, palladium dichlorobis(benzonitrile)),
dichlorobis(1,5-cyclooctadiene)palladium,
di-p-chlorobis(triphenylphosphine)dipalladium,
tetrakis(triphenylphosphine)palladium, or tris(dibenzylidene
acetone)dipalladium. Examples of bases suitable for the reaction
include 0 to 100 equivalents, and preferably 1 to 10 equivalents,
of a nitrogen-containing base such as triethylamine, diethylamine,
or pyridine or inorganic bases such as sodium carbonate, potassium
carbonate, or cesium fluoride, and regarding the solvent, compound
VIII-1 may be derived by treating at -50 to 300.degree. C.,
preferably 10 to 40.degree. C., and more preferably 15 to
30.degree. C., in a hydrocarbon-based solvent such as toluene, an
ether-based solvent such as THF, methyltetrahydrofuran, or ethylene
glycol, an ester-based solvent such as ethyl acetate or isopropyl
acetate, an aprotic polar solvent such as DMF,
1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidone, DMSO, or
acetonitrile, or an alcohol-based solvent such as ethanol,
methanol, IPA, propanol, or butanol.
[0080] Conversion of compound VIII-1 to XI-1 is carried out under
mild conditions of the type whereby polymerization of the
vinylamide moieties of compound XI-1 can be suppressed. Auxiliary
agents that are used are, for example, organic bases typified by
triethylamine, diisopropylethylamine, pyridine, DABCO or the like,
inorganic bases typified by potassium carbonate, potassium
bicarbonate, potassium phosphate, potassium t-butoxide or the like,
and inorganic or organic fluorides such as tetra-n-butylammonium
fluoride, benzyltriethylammonium fluoride, tetraethylammonium
fluoride, potassium fluoride, and cesium fluoride.
[0081] Compound XI-1 can be derived by means of treatment at -50 to
300.degree. C., and preferably 10 to 60.degree. C., in a
hydrocarbon-based solvent such as toluene, an ether-based solvent
such as THF, methyltetrahydrofuran, or ethylene glycol, an
ester-based solvent such as ethyl acetate or isopropyl acetate, an
aprotic polar solvent such as DMF, 1,3-dimethyl-2-imidazolidinone,
1-methyl-2-pyrrolidone, DMSO, or acetonitrile, or an alcohol-based
solvent such as ethanol, methanol, IPA, propanol, or butanol.
WORKING EXAMPLES
[0082] Working examples are presented below in order to facilitate
understanding of the present invention, but without going beyond
the gist thereof, the present invention is not limited to the
following working examples.
[0083] Furthermore, production examples for the raw materials used
in the present invention will be described before the working
examples. When not otherwise specified, the respective procedures
were as follows.
[0084] The reaction processes were carried out specifically at 18
to 25.degree. C. in an inert gas atmosphere (such as nitrogen).
[0085] Concentration of solutions was carried out using a rotary
evaporator under reduced pressure.
[0086] Solvent drying was carried out on, for example, anhydrous
sodium sulfate, and the desiccant was removed by filtration.
[0087] Column chromatography was carried out using a suitable
developing solution, such as chloroform-methanol.
[0088] The structure of the target product was confirmed by proton
nuclear magnetic resonance (.sup.1H-NMR; 400 MHz). .sup.1H-NMR,
when not otherwise specified, involved measurement in deuterated
DMSO (DMSO-d.sub.6) or deuterated chloroform (CDCl.sub.3) with the
chemical shift values expressed as .delta. values (ppm) using
tetramethylsilane (TMS) as a standard and multiple peaks were
indicated as described below.
[0089] s denotes singlet, d denotes doublet, t denotes triplet, m
denotes multiplet, br denotes broad peak, and the magnitude of
signal splitting is represented in units of Hz using the coupling
constant J as a symbol.
Production Example 1
7-iodo-6-nitro-4(3H)-quinazoline: Compound (1)
[0090] 7-chloro-6-nitro-4(3H)-quinazolinone (50.0 g, 222 mmol) and
sodium iodide (332 g, 2216 mmol) were added to N-methylpyrrolidone
(500 mL), and were stirred for 5 h at 170.degree. C.
[0091] The reaction solution was poured into water (1500 mL) and
was stirred for 1 h.
[0092] The precipitated crystals were collected by filtration, and
after washing with water, were dried under reduced pressure to
obtain 7-iodo-6-nitro-4(3H)-quinazolinone (1) (44.7 g, 64%).
[0093] .sup.1H-NMR (DMSO-d.sub.6) ppm: 8.3 (s, 1H), 8.3 (s, 1H),
8.5 (s, 1H), 12.7 (brs, 1H)
Working Example 1
7-iodo-3-(4-methoxybenzyl)-6-nitro-4-quinazolinone: Compound
(2)
[0094] DMF (30 mL) and triethylamine (1.4 mL, 10.5 mmol) were added
to compound (1) of Production Example 1 (3.17 g, 10 mmol), and
after stirring, a solution of 4-methoxybenzyl chloride (1.64 g,
10.5 mmol) in DMF (5 mL) was added; after stirring for 22 h, the
temperature was increased to 50.degree. C., and this was stirred
for an additional 6 h. Water (70 mL) was added to the reaction
solution, the precipitated crystals were collected by filtration,
and after washing with ethanol/water (2/1), dried under reduced
pressure to obtain the target compound (2) (3.91 g, 89%).
[0095] .sup.1H-NMR (DMSO-d.sub.6) ppm: 3.7 (s, 3H), 5.1 (s, 2H),
6.9 (d, 2H, J=9.0 Hz), 7.3 (d, 2H, J=9.0 Hz), 8.4 (s, 1H), 8.6 (s,
1H), 8.7 (s, 1H)
Working Example 2
6-amino-7-iodo-3-(4-methoxybenzyl)-4-quinazoline: Compound (3)
[0096] Ethanol (40 mL), activated carbon (grade: Shirasagi,
purification, 0.16 g), and anhydrous iron chloride (7.5 mg, 0.046
mmol) were added to compound (2) of Working Example 1 (2.02 g, 4.62
mmol), and after heating to 65.degree. C., hydrazine hydrate (584
mg, 9.33 mol) was added and this was stirred for 3 h. After
allowing the reaction solution to cool, the precipitated crystals
were collected by filtration and dried under reduced pressure to
obtain target compound (3) (1.89 g, weight including activated
carbon).
[0097] .sup.1H-NMR (DMSO-d.sub.6) ppm: 3.7 (s, 3H), 5.1 (s, 2H),
5.7 (s, 2H), 6.9 (d, 2H, J=9.0 Hz), 7.3 (d, 2H, J=9.0 Hz), 7.4 (s,
1H), 8.0 (s, 1H), 8.2 (s, 1H)
Working Example 3
N-{7-iodo-3-(4-methoxybenzyl)-4-oxo-3,4-dihydro-6-quinazolinyl}-3-(phenyls-
ulfonyl)propanamide: Compound (4)
[0098] DMF (20 mL), 3-phenylsulfonylpropionic acid (1.04 g, 4.83
mmol), and n-propylphosphonic anhydride, cyclic trimer (50% ethyl
acetate solution; 5.39 g, 8.463 mmol) were added, while chilling on
ice, to compound (3) of Working Example 2 (1.80 g, including the
weight of activated carbon), triethylamine (1.13 mL, 8.06 mmol) was
added dropwise, and this was stirred for 2 h;
3-phenylsulfonylpropionic acid (1.04 g, 4.83 mmol),
n-propylphosphonic anhydride, cyclic trimer (50% ethyl acetate
solution; 5.39 g, 8.463 mmol), and triethylamine (1.13 mL, 8.06
mmol) were again added, and after stirring for 2 h, the reaction
solution was heated to 35.degree. C. and stirred for 2 h. The
reaction solution was filtered, a 10% potassium bicarbonate
solution (30 mL) was added to the filtrate and stirred, and the
precipitated crystals were filtered. The crystals were washed in
suspension with acetonitrile/water (1/1; 30 mL), and were then
washed in suspension with acetonitrile (30 mL) while heating under
reflux; water (10 mL) was added, and after stirring for 15 min at
20.degree. C., the precipitated crystals were filtered and dried
under reduced pressure to obtain target compound (4) (1.80 g, yield
68% from compound (2) of Working Example 1).
[0099] .sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 2.9 (t, 2H, J=7.5
Hz), 3.6 (t, 2H, J=7.5 Hz), 3.7 (s, 3H), 5.1 (s, 2H), 6.9 (d, 2H,
J=8.0 Hz), 7.3 (d, 2H, J=8.0 Hz), 7.7 (m, 2H), 7.8 (m, 1H), 8.0 (d,
2H, J=8.0 Hz), 8.0 (s, 1H), 8.2 (s, 1H), 8.5 (s, 1H), 9.8 (s,
1H)
Working Example 4
N-(7-iodo-4-oxo-3,4-dihydro-6-quinazolinyl)-3-(phenylsulfonyl)propanamide:
Compound (5)
[0100] Compound (4) of Working Example 3 (1.20 g, 1.99 mmol) was
dissolved in trifluoroacetic acid (7 mL), and was stirred for 30
min while heating at reflux. The reaction solution was
concentrated, acetonitrile (5 mL) and water (5 mL) were added, and
this was stirred for 1 h at room temperature.
[0101] The precipitated crystals were collected by filtration, and
were dried under reduced pressure to obtain 1.04 g of crystals.
[0102] Acetonitrile/water (1/1; 10 m L) was added to 1.01 g of the
crystals, triethylamine (0.4 mL) was added, and after stirring for
30 min, the precipitated crystals were collected by filtration and
dried under reduced pressure to obtain the target compound (5)
(0.74 g, 79%).
[0103] .sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 2.8 (t, 2H, J=7.5
Hz), 3.6 (t, 2H, J=7.5 Hz), 7.7 (t, 2H, J=7.5 Hz), 7.8 (t, 1H,
J=7.5 Hz), 8.0 (d, 2H, J=7.5 Hz), 8.0 (s, 1H), 8.1 (s, 1H), 8.2 (s,
1H), 9.8 (s, 1H), 12.3 (brs, 1H)
Working Example 5
N-{4-{(3-Chloro-4-fluorophenyl)amino}-7-iodo-6-quinazolinyl}-3-(phenylsulf-
onyl)propanamide: Compound (6) Hydrochloride
[0104] Toluene (2 mL), phosphorus oxychloride (55 mg, 0.354 mmol),
and N,N'-diisopropylethylamine (36 mg, 0.281 mmol) were added to
compound (5) of Working Example 4 (68 mg, 0.141 mmol), and after
stirring at room temperature, 1,2-dichloroethane (2 mL) was added
and stirred for 4 h at 70.degree. C. After cooling the reaction
solution, the insoluble matter was filtered out, the filtrate was
concentrated, and methylene chloride (1 mL), toluene (1 mL), and a
solution of 3-chloro-4-fluoroaniline (100 mg, 0.687 mmol) in IPA (1
mL) were added. After stirring for 3 h at room temperature,
n-hexane (2 mL) was added and stirred for 1 h, and the precipitated
crystals were filtered and dried under reduced pressure to obtain
hydrochloride of target compound (6) (28 mg, 31%).
[0105] .sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 2.8 (m, 2H), 3.7 (t,
2H, J=8.0 Hz), 7.5 (t, 1H, J=9.0 Hz), 7.7 (m, 2H), 7.8 (t, 1H,
J=7.5 Hz), 8.0 (d, 2H, J=7.5 Hz), 8.1 (dd, 1H, J=3.0, 7.0 Hz), 8.4
(s, 1H), 8.6 (s, 1H), 8.8 (s, 1H), 10.2 (s, 1H), 11.1 (brs, 1H)
Working Example 6
4-(3-Chloro-4-fluoroanilino)-7-iodo-6-nitroquinazoline: Compound
(15-1)
[0106] Compound (1) of Production Example 1 (30.0 g, 94.6 mmol) was
added to toluene (450 mL), and phosphorus oxychloride (13.2 mL, 142
mmol) and N,N-diisopropylethylamine (33.0 mL, 189 mmol) were added
to this suspension, whereupon this was stirred for 12 h at
75.degree. C. The reaction solution was cooled to 2.degree. C., a
solution of 3-chloro-4-fluoroaniline (16.5 g, 114 mmol) in IPA (175
mL) was added dropwise, and this was stirred for 1 h. N-heptane
(150 mL) was added at 2.degree. C., and was stirred for an
additional 3 hours. The precipitated crystal were filtered and
washed with toluene (90 mL.times.2). The resulting crystals were
then washed in a suspension produced using acetonitrile (600 mL)
heated to 80.degree. C., and the crystals were filtered and washed
with acetonitrile (90 mL.times.2). The resulting crystals were
added to acetonitrile (300 mL)-water (300 ml), and triethylamine
(19.8 mL, 142 mmol) was added dropwise at room temperature.
Stirring was then carried out for 1 h at room temperature. The
crystals were filtered and washed with water (90 mL.times.2). Upon
drying under reduced pressure, the target compound (15-1) was
obtained as brown crystals (32.2 g, 76%).
[0107] .sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 7.46 (t, 1H, J=8.8
Hz), 7.79 (m, 1H), 8.14 (dd, 1H, J=2.4, 6.8 Hz), 8.44 (s, 1H), 8.72
(s, 1H), 9.22 (s, 1H), 10.30 (br s, 1H)
Working Example 7
N-4-(3-Chloro-4-fluorophenyl)-7-iodo-4,6-quinazoline diamine:
Compound (15-2)
[0108] Compound (15-1) of Working Example 6 (80.0 g, 180 mmol),
anhydrous ferric chloride (III) (292 mg, 1.80 mmol) and activated
carbon (grade: Shirasagi, purification, 22.5 g) were mixed in
methanol (1600 mL), and hydrazine hydrate (80%; 21.9 mL, 360 mmol)
was added dropwise at 64.degree. C. This was stirred for 2 h at
64.degree. C., THF (960 mL) was added at room temperature, and the
activated carbon was filtered out. About 1800 mL of the solvent was
evaporated off under reduced pressure, methanol (1200 mL) was
added, and about 1200 mL of the solvent was evaporated off under
reduced pressure. This was stirred for 2 h while chilling on ice,
and the precipitated crystals were filtered and washed with
methanol (240 mL). Upon drying under reduced pressure, target
compound (15-2) was obtained as yellow-white crystals (69.4 g,
93%).
[0109] .sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 5.60 (br s, 2H),
7.42 (t, 1H, J=8.8 Hz), 7.52 (s, 1H), 7.80 (ddd, 1H, J=2.4, 6.8,
8.8 Hz), 8.18 (dd, 1H, J=2.4, 6.8 Hz), 8.19 (s, 1H), 8.38 (s, 1H),
9.67 (s, 1H)
Working Example 8
N-{4-{(3-chloro-4-fluorophenyl)amino}-7-iodo-6-quinazolinyl}-3-(phenylsulf-
onyl)propanamide: Compound (6)
[0110] 3-phenylsulfonylpropionic acid (21.7 g, 101 mmol) and
n-propanephosphonic anhydride, cyclic trimer (50% ethyl acetate
solution; 100 mL, 169 mmol) were added to a solution of compound
(15-2) of Working Example 7 (35.0 g, 84.4 mmol) in THF (350 mL),
and triethylamine (22.4 mL, 160 mmol) was added dropwise at
3.degree. C. The reaction solution was warmed to room temperature,
and was stirred for 12 h at room temperature. 2-propanol (175 mL)
was added, water (525 mL) and triethylamine (47.1 mL, 338 mmol)
were then added, and this was stirred for 2 h at 3.degree. C. The
precipitated crystals were filtered and washed with THF/water=1/1
(105 mL.times.2). Upon drying under reduced pressure, the target
compound (6) was obtained as milky-white crystals (50.6 g,
98%).
[0111] .sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 2.81 (t, 2H, J=7.2
Hz), 3.67 (t, 2H, J=7.2 Hz), 7.44 (t, 1H, J=8.8 Hz), 7.77 (m, 4H),
7.99 (m, 2H), 8.13 (dd, 1H, J=2.4, 6.4 Hz), 8.36 (s, 1H), 8.43 (s,
1H), 8.60 (s, 1H), 10.02 (s, 1H), 10.11 (s, 1H)
Working Example 9
N-{4-(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl-
)-1-butynyl]-6-quinazolinyl}-3-(phenylsulfonyl)propanamide:
Compound 8
[0112] A solution of palladium (II) acetate (110 mg, 0.49 mmol) and
triphenylphosphine (258 mg, 0.98 mmol) in DMSO (100 mL) was stirred
for 30 min at room temperature, whereupon compound (6) of Working
Example 5 (10.0 g, 16.4 mmol),
1-(1,1-dimethyl-2-propynyl)-4-methylpiperazine (7) (3.27 g, 19.6
mmol) and copper (I) iodide (93.0 mg, 0.49 mmol) were added, and
triethylamine (5.70 mL, 40.9 mmol) was added dropwise. After
stirring for 3 h, the reaction solution was added dropwise to water
(100 mL), and was stirred for one additional hour. The precipitated
crystals were filtered and washed with water, before washing the
crystals as a suspension in IPA/water (1/1; 200 mL).
[0113] The precipitated crystals were filtered and dried under
reduced pressure to obtain target compound (8) (yield of 96% from
compound (6) of Working Example 5, yield of 80% from compound
(7)).
[0114] .sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.4 (s, 6H), 2.2 (s,
3H), 2.3 (brs, 4H), 2.6 (brs, 4H), 2.8 (t, 2H, J=7.5 Hz), 3.7 (t,
2H, J=7.5 Hz), 7.5 (t, 1H, J=9.0 Hz), 7.7 (m, 5H), 8.0 (m, 2H), 8.2
(dd, 1H, J=3.0, 7.0 Hz), 8.50 (s, 1H), 8.62 (s, 1H), 9.87 (s, 1H),
9.96 (s, 1H)
Working Example 10
N-{[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-
-1-butynyl]-6-quinazolinyl}acrylamide: Compound (9)
[0115] Tetra-n-butylammonium fluoride (1 mol/L, THF solution; 46.2
mL, 46.2 mmol) was added dropwise to a solution of compound (8) of
Working Example 9 (5.00 g, 7.70 mmol) in THF (100 mL). After
stirring for 12 h, a 10% potassium bicarbonate aqueous solution (50
mL) was added to the reaction solution, and decanted. The organic
layer was washed with 10% potassium bicarbonate aqueous solution
(50 mL), and was then washed with 10% sodium chloride aqueous
solution (50 ml). IPA (100 mL) was added to the organic layer, and
100 mL of the solvent was then evaporated off under reduced
pressure. Next, water (100 ml) was added dropwise, and after
stirring for 1 h while chilling on ice, the precipitated crystals
were filtered, washed twice with IPA/water (1/1; 20 mL), and dried
under reduced pressure to obtain target compound (9) (3.24 g,
83%).
[0116] .sup.1H-NMR (DMSO-d.sub.6) .delta. ppm: 1.4 (s, 6H), 2.2 (s,
3H), 2.4 (brs, 4H), 2.6 (brs, 4H), 5.8 (d, 1H, J=11.0 Hz), 6.3 (d,
1H, J=17.0 Hz), 6.6 (dd, 1H, J=11.0, 17.0 Hz), 7.5 (t, 1H, J=9.0
Hz), 7.8 (m, 2H), 8.2 (dd, 1H, J=2.0, 7.0 Hz), 8.6 (s, 1H), 8.7 (s,
1H), 8.9 (s, 1H), 10.0 (s, 1H)
Working Example 11
N-{[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-
1-butynyl]-6-quinazolinyl}acrylamide: Compound (9)
[0117] Potassium tert-butoxide (28.0 mg, 0.25 mmol) was added at
room temperature to a solution of
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl}-3-(phenyloxy)propanamide: compound
(8-2) (50.0 mg, 0.08 mmol) synthesized in the same manner as
compound (8) of Working Example 9 in DMF (1 mL), and was stirred
for 1 h at room temperature.
[0118] Ethyl acetate (10 mL) and 10% sodium chloride aqueous
solution (5 mL) were added to the reaction solution, and decanting
was performed. The aqueous layer was subjected to extraction using
ethyl acetate (5 mL). The organic layers were mixed, and were then
washed with 10% sodium chloride aqueous solution (5 mL.times.2).
After drying on anhydrous sodium sulfate, the solvent was
evaporated off under reduced pressure, and the residue was purified
by silica gel column chromatography (methylene chloride methylene
chloride/methanol=4/1) to obtain
N-{[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazinyl-
)1-butynyl]-6-quinazolinyl}acrylamide compound (9) (20.0 mg, 47%)
as yellow crystals.
Reference Example 1
Synthesis of
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4-methyl-1-piperazin-
yl)-1-butynyl]-6-quinazolinyl}-3-(phenylsulfonyl)propanamide,
compound (8), by means of a reaction between
1-(1,1-dimethyl-2-propynyl)-4-methylpiperazine, compound (7), with
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-iodo-6-quinazolinyl}-3-(phenylsul-
fonyl)propanamide compound (6),
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-bromo-6-quinazolinyl}-3-(phenylsu-
lfonyl)propanamide, compound (6-1), or
N-{4-[(3-chloro-4-fluorophenyl)amino]-7-chloro-6-quinazolinyl}-3-(phenyls-
ulfonyl)propanamide, compound (6-2)
[0119] Each of the reactions was carried out under the same
conditions as in Working Example 9, and analysis was carried out
under the HPLC conditions indicated below after sampling the
respective reaction solutions at a determinate time. TABLE-US-00001
TABLE 1 HPLC conditions Column: L-column ODS diameter 4.6 mm
.times. 250 mm Mobile layer: 0.1% trifluoroacetic acid acetonitrile
solution/0.1% trifluoroacetic acid aqueous solution = 40/60 (volume
ratio) Flow rate: 1 mL/min Detection wavelength: 254 nm Retention
time: Compound (6) 11.2 min, Compound (6-1) 11.3 min, Compound
(6-2) 11.2 min, 8 6.2 min HPLC analysis results HPLC percent
surface area resulting from the reaction of compound (6) and
compound (7): After reacting for 1 h: Compound (6) 5.3%, Compound
(8) 91.2% After reacting for 3 h: Compound (6) not detected by
HPLC, Compound (8) 94.5% Compound (8) obtained by treatment using a
procedure analogous to Working Example 6 after reacting for 3 h:
Isolated yield 96%. HPLC percent surface area resulting from the
reaction of compound (6-1) and compound (7): After reacting for 1
h: Compound (6-1) 58.9%, Compound (8) 38.7% After reacting for 23
h: Compound (6-1) 40.3%, Compound (8) 55.7% HPLC percent surface
area resulting from the reaction of compound (6-2) and compound
(7): After reacting for 1 h: Compound (6-2) 98.2%, Compound (8) not
detected by HPLC After reacting for 10 h: Compound (6-2) 96.3%,
Compound (8) 0.2% As described above, iodoquinazoline compound (6)
exhibited high reactivity in the carbon-carbon bond production
reaction using Pd catalyst in comparison to the corresponding bromo
compound (6-1) or chloro compound (6-2).
INDUSTRIAL APPLICABILITY
[0120] By virtue of the present invention, a novel quinazoline
derivative can be provided for use as an intermediate in the
production of pharmaceutical products such as cancer drugs.
Furthermore, the quinazoline derivative can be used in order to
provide an efficient production method for pharmaceutical
products.
[0121] Note that this application was filed claiming priority from
JP-2003-398442.
* * * * *